Specific signs
The anchor question: this one objective finding points somewhere. Where? A persistently low alkaline phosphatase, a CK that won't settle, a urate that barely registers, transaminases without a liver diagnosis, cystic kidneys, a dysmorphic feature, a family pattern the panel didn't explain. The sign sets the pretest probability. The work is picking the test it has earned, and holding the prescription it argues against.
Who this cohort covers
Adults with a single objective finding and no unifying diagnosis: a lab abnormality that repeats, an imaging finding, a dysmorphic or skin feature, or a striking family pattern with uninformative testing. Many have been told the number is a quirk, and some of them are right. Others have a nameable, sometimes treatable, disease, and a drug that should wait until it's named.
The sign is easy to see and easy to pass over. In a ten-year review of rheumatology and internal medicine inpatients at six French university hospitals, 70.8% of adults with persistently low ALP who were given a bisphosphonate never had an ALP measured before it started, and 20.8% were treated despite a low value already on file.1 Bisphosphonates and denosumab are on the avoid list in hypophosphatasia.2 And the yield is real: among adults with persistently low ALP and secondary causes excluded, 40 of 85 (47%) carried an ALPL variant.3 When a sign earns broader sequencing, adult exome yield runs 17.5% overall, 23.9% at ages 18 to 30 and 10.4% after 30.4
Care map
| Role | Year 1, Establish | Year 2, Treat | Year 3, Sustain |
|---|---|---|---|
| Anchor | Confirm the sign is real and persistent: repeat it, and read it against a properly defined reference range.3 5 Medications, exercise and family history around the finding. Hold any drug the sign argues against until it is explained: no antiresorptive with a persistently low ALP until hypophosphatasia is excluded.1 2 | Act on the result. Route a diagnosis to its cohort, start cascade testing, put the genotype on the problem list. | Annual review. If the workup was negative, write down what was excluded and what would reopen it. |
| Genetics | Match the test to the sign. Single gene or a small panel when the sign is specific and the pretest probability is high: ALPL when ALP is persistently low, especially with ALP below 25 IU/L and PLP above 180 nmol/L;3 6 SLC22A12 and SLC2A9 for renal hypouricemia, though the diagnosis doesn't require them.7 Exome or genome when the sign sits in a broader picture. Adult diagnoses cluster in nervous system, skeletal, head and neck and growth phenotypes, and a positive family history did not predict yield.4 With a congenital anomaly or intellectual disability in the history, we borrow the ACMG pediatric guideline: consider exome or genome as a first- or second-tier test.8 | Cascade testing once a variant is classified. Genetics consult for a VUS, a result that doesn't fit, or two diagnoses at once; dual Mendelian diagnoses made up 7% of adult exome diagnoses.4 | Ask for reanalysis of a nondiagnostic exome or genome. Pooled reanalysis yield is about 10%, mostly from new gene-disease literature.9 |
| Specialists | Neuromuscular to consider muscle biopsy when an EFNS criterion is met: CK at or above 3× the upper limit, a myopathic EMG, or age under 25.5 Nephrology for cystic kidneys or nephropathy of unknown cause, where exome yield was 23.9% and 17.1% respectively.10 Hepatology after a CK and the standard hepatocellular workup come back clean.11 12 | Bone and mineral specialist once HPP is confirmed; the hypophosphatasia cohort takes it from there. Other confirmed diagnoses go to their cohort. | Follow-up per diagnosis. No open-ended referral cycle for a sign that has been explained. |
| Diagnostics | Low ALP: repeat ALP with serum PLP; the proposed cutoffs for predicting an ALPL variant are ALP below 25 IU/L and PLP above 180 nmol/L.6 High CK: repeat, and define hyperCKemia as above 1.5× the upper limit.5 Low urate: serum urate with fractional excretion of uric acid; renal hypouricemia is urate at or below 2.0 mg/dL on repeat testing with a raised FEUA, after excluding other causes (Fanconi syndrome, Wilson disease, SIADH, drugs).7 Unexplained ALT and AST: CK first, because transaminases rise and fall with muscle injury, as shown in inflammatory myopathy;11 then screen for hemochromatosis, autoimmune hepatitis, Wilson disease and alpha-1 antitrypsin deficiency.12 | Consider muscle biopsy when an EFNS criterion is met.5 Targeted imaging when the diagnosis calls for it. | Repeat the sign only when the trend would change management. |
| Therapies | Low ALP: no bisphosphonate or denosumab until HPP is excluded.1 2 Renal hypouricemia: counsel on exercise-induced acute kidney injury and stones; fluids, and citrate alkalinization for stone prevention.7 Mildly high CK: up to 20% of healthy people run one, and on its own it needn't cost the patient a statin.5 | Disease-specific therapy through the destination cohort. | |
| Behavioral health and nutrition | Name the uncertainty plainly: a sign under investigation is not yet a diagnosis. | Genetic counseling before and after sequencing. | As needed. |
| Community | Patient organization for the diagnosis, once there is one. |
Visit one
The map above is the evidence. This is what to do with the patient in the room. Each line comes from the Year 1 column and carries the same citations.
| Ask | Every prior value of the sign, with dates, to establish persistence.3 Medications, recent exercise, and whether an antiresorptive or a statin has been started or proposed.1 5 For low ALP: musculoskeletal pain, dental problems, stress fractures.3 For low urate: exercise-related flank pain or kidney injury, and stones.7 A three-generation pedigree for the same finding. |
| Examine | Strength and muscle bulk when CK is high. Dysmorphology, skin and growth. Write down what you see as specific phenotype terms (HPO), the way the adult exome series coded its patients.4 |
| Order | Repeat the sign. Low ALP: ALP with PLP.6 High CK: repeat CK, read against the 1.5× definition.5 Low urate: urate with FEUA.7 High transaminases: CK, then the hemochromatosis, autoimmune, Wilson and AAT screen.11 12 Targeted gene testing when the sign is specific; exome or genome when it isn't.3 4 8 |
| Refer | Neuromuscular by the EFNS criteria.5 Nephrology for cystic or unexplained kidney disease.10 Genetics for a broad picture or a result that doesn't fit.4 Where: the esoteric assays, clinical expertise and specialist rosters. |
| Tell the patient | What the sign might mean and what it might not. Why the bisphosphonate waits, if one was planned.1 2 That a negative test is a result, and that sequencing data can be looked at again later.9 |
| Document | The sign with every value and date, the reference range used, what was held and why, the tests ordered, and the reanalysis date if sequencing is negative. |
Roster for this cohort
Drawn from the esoteric assays roster (biochemical genetics, sequencing and reanalysis labs), clinical expertise (genetics consults and variant interpretation), procedural studies (EMG), advanced imaging, the specialist roster (neuromuscular, nephrology, hepatology, endocrinology), and genetic counselors from the counselor roster. Forming; propose entries in the cohort channel.
Readings
- GeneReviews: Hypophosphatasia, University of Washington, updated 2025.
- ACMG: points to consider in the reevaluation and reanalysis of genomic test results (Deignan et al., Genet Med 2019, doi:10.1038/s41436-019-0478-1).
- ACMG: exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability (reference 8), the closest guideline we have for adults with the same history.
- EFNS guideline on pauci- or asymptomatic hyperCKemia (reference 5), ACG guideline on abnormal liver chemistries (reference 12), and the first clinical practice guideline for renal hypouricemia (reference 7).
References
- Larid G, Vix J, Preuss P, et al. Detection of hypophosphatasia in hospitalised adults in rheumatology and internal medicine departments: a multicentre study over 10 years. RMD Open. 2024;10(2):e004316. doi:10.1136/rmdopen-2024-004316
- Dahir KM, Nunes ME. Hypophosphatasia. In: GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. Updated 2025. NBK1150
- Tornero C, Navarro-Compán V, Tenorio JA, et al. Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia? Orphanet J Rare Dis. 2020;15(1):51. doi:10.1186/s13023-020-1315-y
- Posey JE, Rosenfeld JA, James RA, et al. Molecular diagnostic experience of whole-exome sequencing in adult patients. Genet Med. 2016;18(7):678-685. doi:10.1038/gim.2015.142
- Kyriakides T, Angelini C, Schaefer J, et al. EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. Eur J Neurol. 2010;17(6):767-773. doi:10.1111/j.1468-1331.2010.03012.x
- Tornero C, Navarro-Compán V, Buño A, et al. Biochemical algorithm to identify individuals with ALPL variants among subjects with persistent hypophosphatasaemia. Orphanet J Rare Dis. 2022;17(1):98. doi:10.1186/s13023-022-02253-5
- Nakayama A, Matsuo H, Ohtahara A, et al. Clinical practice guideline for renal hypouricemia (1st edition). Hum Cell. 2019;32(2):83-87. doi:10.1007/s13577-019-00239-3
- Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11):2029-2037. doi:10.1038/s41436-021-01242-6
- Dai P, Honda A, Ewans L, et al. Recommendations for next generation sequencing data reanalysis of unsolved cases with suspected Mendelian disorders: a systematic review and meta-analysis. Genet Med. 2022;24(8):1618-1629. doi:10.1016/j.gim.2022.04.021
- Groopman EE, Marasa M, Cameron-Christie S, et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019;380(2):142-151. doi:10.1056/NEJMoa1806891
- Mathur T, Manadan AM, Thiagarajan S, et al. Serum transaminases are frequently elevated at time of diagnosis of idiopathic inflammatory myopathy and normalize with creatine kinase. J Clin Rheumatol. 2014;20(3):130-132. doi:10.1097/RHU.0000000000000038
- Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112(1):18-35. doi:10.1038/ajg.2016.517
References retrieved from PubMed on 2026-10-30. Care maps are peer-authored clinical frameworks for network members, not individualized medical advice, and are reviewed at each yearly cycle.